ABSTRACT/PROJECT SUMMARY Linked VA Merit Overall Research Strategy: Traumatic brain injury (TBI) from Open Field Blast or repeat mild impact to human tau transgenic mice (htau) will induce Alzheimer-relevant, tau-dependent pathology rescued by tau suppression or treated with therapeutics that block tau aggregation. TBI-induced tau-related ultrastructural changes will be analyzed in brains from both mice and Veterans exposed to blast, and plasma biomarkers for TBI and/or Alzheimer-pathology will be identified in mice and validated in humans. TBI is a risk factor prevalent in Veterans, increasing the risk for neurodegenerative diseases such as post- traumatic epilepsy, Parkinson?s and tauopathies [chronic traumatic encephalopathy (CTE) and Alzheimer disease (AD)]. Despite millions at risk, there is a paucity of sensitive and practical blood biomarkers that predict adverse long-term outcomes and track disease progression to monitor efficacy of interventions during the extended prodromal period. The overarching goal of this proposal is to fill this knowledge gap. Preliminary data show that TBI-associated neurodegeneration and neuroinflammation are tau-dependent. The levels of the neuroinflammatory proteins GFAP and AQP4 in astrocytes robustly parallels disease severity in the brains of TBI subjects (linked PI: McKee). Further, our data in htau mice and humans, support the hypothesis that the level of these proteins in plasma extracellular vesicles (EVs) parallel brain pathology. Also data suggest that EVs isolated from the brain contain ptau (oligomers and fragments) and markers of dendritic and axonal degeneration (neurogranin, SNAP-25, neurofilaments) and levels plasma EVs. Finally, we show that in htau mice, an intranasally delivered inhibitor of pathogenic tau aggregation reduces CNS tau accumulation in htau mice. In Aim 1 we propose to use our repetitive mild TBI (rmTBI) model to test the hypothesis that plasma EV epitopes evolve over time and reflect glial responses, neurodegeneration and tauopathy. In Aim 2 we validate the accuracy of the biomarkers, testing the hypotheses that (A) specific tau aggregates promote persistent gliosis and degeneration in TBI corresponding to the EV biomarkers , and (B) conversely, that modulation of tau aggregation with a tau aggregation inhibitor, reduces tau oligomers, gliosis and tauopathy, similarly affecting the EV biomarkers. Our plasma samples are then used by (linked project: Dr. Xia) to use proteomics to more fully characterize altered tau in brain EVs post TBI and to identify other persistent brain EV biomarkers for post-TBI neurodegeneration and tauopathy. Aim 3 seeks to extend our EV biomarker approach using tissue (linked project: Dr. Gu), from the same mice with or without the transgene exposed to blast injury that models Veteran exposure and drives neurodegeneration. This aim also includes the evaluation (and sharing) of human plasma from patients with AD, MCI or TBI from all four VA sites. Collectively these studies should produce strong candidate surrogate blood biomarkers, offering a new and accessible window to the pathogenic events leading to CTE and AD. This type of surrogate blood biomarker should enable the development of treatments for CTE and AD and have a high impact on long-term Veteran health and related costs.